UBR4 is an E3 ubiquitin ligase that serves as a central hub for multiple protein quality control pathways in the cytoplasm 1. As a component of the N-end rule pathway, UBR4 recognizes proteins with destabilizing N-terminal residues and catalyzes their ubiquitination and degradation, though it cannot ubiquitinate N-terminally acetylated proteins 2. UBR4 functions as part of several distinct quality control complexes: with UBR5, it assembles heterotypic Lys-11/Lys-48-linked ubiquitin chains on aggregated proteins for proteasomal degradation; with KCMF1, it targets oxidized proteins bearing Arg-CysO3(H) degrons for autophagy via Lys-63/Lys-27-linked chains; and within the SIFI complex, it degrades components of mitochondrial stress response pathways 31. The protein acts as an E4 ligase that recognizes mono-ubiquitinated orphan subunits from multi-protein complexes and extends them with K48-linked poly-ubiquitin chains 14. Structurally, UBR4 forms a massive 1.3-megadalton ring complex with cofactors KCMF1 and CALM1 4. Disease associations include episodic ataxia, early dementia, and cancer, where UBR4 promotes tumor growth by regulating mitochondrial quality control 56.